The long-term goal of this grant is to further our understanding of the molecular regulation of hair follicle development and cycling, with the hope that this new knowledge will provide clues to the pathogenesis of hair follicle disorders and lead to new approaches to therapy. The follicle is a powerful model for studying pathways controlling organ development and regeneration. Throughout much of adult life, follicles cycle through an active growth phase, called anagen;a regression phase, catagen;and a resting phase, telogen. Numerous factors and pathways are required for proper hair follicle development and cycling: our work has centered largely on the Hedgehog (Hh)/Gli pathway. Normally, the Hh/Gli pathway is repressed since the Hh receptor Ptch1 inhibits Smo, a key signal transducer in this pathway. Secreted Hh binds to Ptch1 and inhibits it function, relieving the inhibition of Smo, which is then free to activate signaling and ultimately modulate gene expression via Gli transcription factors. The Hh/Gli pathway has well-established functions during embryonic and postnatal hair follicle growth, where it provides a major proliferative stimulus to epithelial cells as they rapidly expand to build the mature, anagen hair follicle. However, essentially nothing is known of the role of Hh/Gli activity in a small subset of cells in the resting, telogen follicle, which was just recently discovered. In addition, the function of sustained Hh/Gli signaling in mature, anagen hair follicles is also not known. We propose to address both of these questions using several complementary in vivo approaches, which will enable us to block Hh/Gli signaling at different levels in the pathway, and at specific times during the hair cycle. We also propose to test the role of the transcriptional repressor Bmi1, a Hh/Gli target in other organs, in hair follicle biology. The results of these studies will fill in major gaps in our understanding of how Hh/Gli signaling contributes to the complex regulation of hair follicle biology, and may yield clues into the pathogenesis of hair follicle disorders. More globally, they will provide fundamental insight into pathways that are utilized by many other organs for growth and regeneration, and are commonly deregulated in cancer. Finally, since several Hh pathway inhibitors are currently in clinical trials, these studies are timely as they will lead to a better understanding of potential toxicities associated with the use of these drugs in patients. PUBLIC HEALTH RELEVANCE: Abnormalities in the hair follicle and related structures are responsible for many common skin diseases and hair loss disorders. The experiments in this grant will increase our understanding of the control mechanisms that regulate hair follicle growth and development. This knowledge should lead to new and improved treatments for hair follicle-related skin diseases.